Studies On The Synthesis And Antimicrobial Activities Of Water-soluble 1, 5-benzothiazepines And Their Reductive Products

1,5-benzothiazepines are a kind of seven-membered heterocycle compounds and have important physiological activities.Some of their derivatives have been used in clinic as antianxiety drugs,hypnogenetics and cardiovascular medicines.Therefore,their synthesis, structures and phannacological activities have been attracted wide attentions by human beings.Whether a compound can be from a pure chemical entity to a successful drug is evaluated by its efficacy,pharmacokineties,safety,and other aspects.So it should have a certain extent of fat-solubility and water-solubility.Many bioactive compounds haven't the natures of the absorption,distribution,metabolism and elimination so they can not be applied in clinic.Besides that,the drugs which is not only used in the oral administration,but also the injection or the infusion frequently,so the medicine is more requested to be having a certain of water-solubility.As far as most of the compounds of 1,5-benzothiazepine which have antibacterial activity aren't easily dissolved by water,we need to use a greater amour of the drug to achieve it's pharmacodynamics because the drug has a poor polarity.So the compounds are hard to be practical medicine or its applications are limited without the modification of hydrophilic groups.In order to overcome their bad water-soluble and improve their antibacterial activity,a class of water-soluble carboxy-substituted 1,5-benzothiazepine:the potassium salts of 2,3—dihydro-1,5-benzothiazepine-2-carboxylic acid and the ethyl esters 2,3-dihydro-7-chloro-1,5—benzothiazepine-2-carboxylic acid are designed and synthesized in this paper.The structures of these new compounds are determined by IR,~1H NMR,MS and Elementary Analysis;In order to evaluate the relationship between the imine and ester functional groups and their antibacterial activity,we also reduct the double bonds of the imine in the 2,3-dihy-dro -7-chloro-1,5-benzothiazepine-2-carboxylic acid ester.The antibacterial activities of the 20 new compounds have been studied.The antibacteriaon activities were tested by Escherichia coli,Staphylococcus aureus,White aureus and Candida albicans(fungi).This job will be having an important significance for the heterocyclic drugs which has the special feature and the new physiological activity. This thesis including the following major parts:1.15 new compounds:the potassium salts of 2,3-dihydro(-7-chloro)-1,5-benzothiaz-epine -2-carborylic acid and the ethyl esters of 2,3-dihydro.7-chloro-1,5-benzothiazepine--2-arboxylic acid were synthesized by several reaction steps which is Friedel-Crafts acylation reaction,esterification reaction,Michael addition reaction,hydrolysis reactions starting from benzene.The structures of these new compounds were determined by IR,~1H NMR,MS and Elementary Analysis.Further more,the key steps of the synthesis of ethyl esters of 2,3-dihy-dro -7-chloro-1,5-benzothiazepine-2-carboxylic acid was deeply carried out and investigated.2.5 new compounds:the ethyl esters of 2,3,4,5-tetrahydro-7-chloro-1,5-benzothia-zepine -2-carboxylic acid were synthesised by the reduction of the imine double bond of the ethyl esters of 2,3-dihydro-7-chloro-1,5-benzothiazepine-2-carboxylic acid using cyano sodi-um borohydrid.The structures of these compounds are determined by IR,~1H NMR,MS and Elementary Analysis.3.The antibacterial activity of the above 20 new compounds were tested in vitro by using of filter paper method.The results show that:the three kinds of compounds have significant inhibition for fungi(Candida albicans).The majority of the compounds belong to highly sensitive compounds to fungi.This results will have the important guiding to the anti-fungi medicines.And they also have a strong inhibitory effective on Staphylococcus aureus and White aureus but less effective on Escherichia coli.